Process for the preparation of racemic citalopram and/or s-or r-citalopram by separation of a mixture of r-and s-citalopram

ABSTRACT

The invention relates to a process for the preparation of racemic citalopram free base or an acid addition salt thereof and/or R- or S-citalopram as the free base or an acid addition salt thereof by separation of a mixture of R- and S-citalopram with more than 50% of one of the enantiomers into a fraction consisting of racemic citalopram and/or a fraction of S-citalopram or R-citalopram characterized in that i) citalopram is precipitated from a solvent as the free base or as an acid addition salt thereof; ii) the precipitate formed is separated from the mother liquor; iia) if the precipitate is crystalline it is optionally recrystallised one or more times to form racemic citalopram, and then optionally converted into an acid addition salt thereof; iib) if the precipitate is not crystalline, steps i) and ii) are optionally repeated until a crystalline precipitate is obtained and the crystalline precipitate is recrystallised one or more times to form racemic citalopram, and then optionally converted into an acid addition salt thereof; iii) the mother liquor is optionally subjected to further purification and S-citalopram or R-citalopram is isolated from the mother liquor and optionally converted into an addition salt thereof.

[0001] The invention relates to a process for the preparation of racemiccitalopram and/or S- or R-citalopram by separation of a mixture of R-and S-citalopram with more than 50% of one of the enantiomers into; afraction of racemic citalopram and/or a fraction of S-citalopram orR-citalopram containing low amounts of the other enantiomer. Theinvention also relates to a process for the preparation of racemic aswell as enantiomerically pure citalopram from the compoundR-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile.

BACKGROUND OF THE INVENTION

[0002] S-citalopram (escitalopram) is the active component of theproduct citalopram, which is a racemic mixture of the R- andS-enantiomers. The compound is a valuable antidepressant of theselective serotonin reuptake inhibitor (SSRI) type.

[0003] Both racemic citalopram and S-citalopram are marketed asantidepressant agents.

[0004] It has now surprisingly been found that a mixture of R- andS-citalopram containing more than than 50% of one or the enantiomers,i.e a non-racemic mixture, may be separated into a fraction of racemiccitalopram and a fraction of S- or R-citalopram by precipitation ofcitalopram as the free base or as an acid addition salt thereof. Thesurplus of S-citalopram or R-citalopram may be isolated from the motherliquor of the precipitation.

[0005] This is an important and very useful process, in particularbecause it allows the preparation of racemic citalopram and S-citalopramfrom mixtures of R- and S-citalopram obtained from manufacturingprocesses which result in mixtures which do not meet the specificationsof the marketing approval of neither racemic citalopram nor S-citalopram(in escitalopram, the amount of R-citalopram compared to S-citalopramshould be less than 3%, preferably less).

[0006] S-citalopram may be prepared by separation of the R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(the R- and S-diol) followed by ring closure of the S-diol withretention of configuration, as described in EP-B1-347 066.

[0007] Other processes for the preparation of S-citalopram includingchromatographic separation of enantiomers are also available. It is forexample possible to separate the corresponding bromo-derivative,1-(4-Bromo-2-hydroxymethylphenyl)-4-dimethylamino-1-(4-fluorophenyl)butan-1-olfrom the corresponding R-diol, followed by ring closure with retentionof configuration and cyanation to form S-citalopram. Cyanation processesfor citalopram are well known and have been described in US 4.136.193,WO 00/11926 and WO 00/13648.

[0008] Depending on the specific process used and the conditions used,the enantiomeric purity of the S-citalopram product obtained may have tobe improved.

[0009] Other processes for stereo-selective synthesis of S-citaloprammay also result in mixtures of R-and S-citalopram which do not fulfilthe specifications of the marketing approval of S-citalopram.

[0010] Thus, according to one aspect of the invention, the inventionprovides an easy way to improve the enantiomeric purity of S-citalopramobtained by such processes.

[0011] During the production of S-citalopram by chromatographicseparation of R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrilefollowed by ring closure ofS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile,the R-enantiomer of formula (I)

[0012] is formed as a by-product.

[0013] It has now been found that ring closure of a compound of formulaI in an acidic environment provides a reaction mixture containing asurplus of S-citalopram compared to R-citalopram. In other words, ringclosure in an acidic environment proceed with partial inversion ofconfiguration.

[0014] Accordingly, the by-product of formula (I) may be used for thepreparation of S-citalopram and racemic citalopram and the method forthe production of S-citalopram has thereby become more rational and moreeconomical in the utilisation of reagents and resources.

SUMMARY OF THE INVENTION

[0015] Thus, the present invention relates to a process for thepreparation of racemic citalopram free base or an acid addition saltthereof and/or R- or S-citalopram as the free base or an acid additionsalt thereof by separation of a mixture of R- and S-citalopram with morethan 50% of one of the enantiomers into a fraction consisting of racemiccitalopram and/or a fraction of S-citalopram or R-citalopramcharacterized in that

[0016] i) citalopram is precipitated from a solvent as the free base oras an acid addition salt thereof;

[0017] ii) the precipitate formed is separated from the mother liquor;

[0018] iia) if the precipitate is crystalline it is optionallyrecrystallised one or more times to form racemic citalopram, and thenoptionally converted into an acid addition salt thereof;

[0019] iib) if the precipitate is not crystalline, steps i) and ii) areoptionally repeated until a crystalline precipitate is obtained and thecrystalline precipitate is optionally recrystallised one or more timesto form racemic citalopram, and then optionally converted into an acidaddition salt thereof;

[0020] iii) the mother liquor is optionally subjected to furtherpurification and S-citalopram or R-citalopram is isolated from themother liquor and optionally converted into an acid addition saltthereof.

[0021] According to one specific embodiment, the invention relates to amethod for the preparation of racemic citalopram free base or an acidaddition salt thereof using the process described above.

[0022] According to another specific embodiment, the invention relatesto a method for the preparation of R- or S-citalopram free base or anacid addition salt thereof using the process described above.

[0023] The acid used for precipitation of a citalopram salt in step i)is an acid which may precipitate a mixture of R- and S-enantiomer andleave the mother liquor enriched with either the S- or R-enantiomer ofcitalopram. One such acid is hydrobromic acid.

[0024] According to a preferred embodiment of the invention, the freebase of citalopram or the hydrobromide salt of citalopram isprecipitated, preferably in crystalline form in steps i) and ii).

[0025] According to another embodiment of the invention, the mixture ofR-and S-citalopram used in step i) contains more than 50% ofS-citalopram, or more preferred more than 90% of S-citalopram.

[0026] In step iii) S-citalopram (or R-citalopram) may be is isolatedfrom the mother liquor by the evaporation of the mother liquor andthereafter optionally the conversion of S-citalopram (or R-citalopram)into an acid addition salt thereof, preferably the oxalate salt.

[0027] Alternatively, if the mother liquor obtained from theprecipitation is acidic, S-citalopram (or R-citalopram) may be isolatedfrom the mother liquor by basifying the mother liquor, followed by phaseseparation, or extraction with a solvent and evaporation of the solvent,and thereafter optionally conversion of S-citalopram (or R-citalopram)into an acid addition salt thereof, preferably the oxalate salt.

[0028] The mother liquor, extracts thereof, or the phase containing R-or S-citalopram may be subjected to conventional purification processes(such as treatment with active carbon, chromatography, etc.) and/or itmay be subjected to further precipitations as in step i)-ii) abovebefore R- or S-citalopram is isolated.

[0029] The mixture of R- and S-citalopram with more than 50% of theS-enantiomer may be prepared from a mixture of R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrilewith more than 50% of the S-enantiomer by formation of a labile estergroup and thereafter ring closure in a basic environment.

[0030] In another embodiment of the invention, the mixture of R- andS-citalopram with more than 50% of the R-enantiomer is prepared from amixture of R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrilewith more than 50% of the R-enantiomer by formation of a labile estergroup and thereafter ring closure in a basic environment.

[0031] In a further embodiment of the invention, the mixture of R- andS-citalopram with more than 50% of the S-enantiomer is prepared from amixture of R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrilewith more than 50% of the R-enantiomer by ring closure in presence of anacid.

[0032] In still a further embodiment of the invention, the mixture of R-and S-citalopram with more than 50% of the R-enantiomer is prepared froma mixture of R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrilewith more than 50% of the S-enantiomer by ring closure in presence of anacid.

[0033] Preferably, the enantiomeric purity of the starting materialR-4-[4(dimethylamino)-1-(4′fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrileis more than 90%.

[0034] The acid used in the acidic ring closure reaction may suitably bea mineral acid such as H₂SO₄ or H₃PO₄, a carboxylic acid, a sulfonicacid or a sulfonic acid derivative.

[0035] Whenever used in this document, racemic mixture or racemiccitalopram means a 1:1 mixture of R- and S-citalopram. Non-racemicmixtures or non-racemic citalopram means mixtures which do not containR- and S-citalopram as a 1:1 mixture.

[0036] Citalopram means a mixture of R- and S-citalopram. Citalopramenantiomer or isomer means either S- or R-citalopram.

[0037] As used in this description, precipitation means forming aprecipitate in the form of crystals, an amorphous solid or an oil from asolvent. In the present description, a precipitate means an oil, anamorphous solid or crystals.

[0038] As used herein, mother liquor means the solvent remaining afterremoval or separation from the precipitate.

DETAILED DESCRIPTION OF THE INVENTION

[0039] As mentioned above processes for the preparation of thecitalopram molecule may result in a mixture of R-and S-citalopram whichis not acceptable for pharmaceutical use. According to the invention, asurprisingly efficient process for the separation of such mixtures intoa racemic fraction and a fraction of S-citalopram or R-citalopram hasbeen found. This new process involves precipitation of citalopram freebase or an acid addition salt thereof as an oil, an amorphous solid orin crystalline form from a solvent, and isolation of S-citalopram (orR-citalopram) from the mother liquor of the precipitation process.

[0040] The precipitation of the citalopram free base may be carried outby obtaining or dissolving the non-racemic mixture of R- andS-citalopram in a suitable solvent, optionally by applying heating, andthen allowing the solution to cool. The precipitate is then separatedfrom the mother liquor, preferably by filtration or decanting. If theprecipitate is crystalline, the crystals are optionally recrystallisedand the free base of racemic citalopram may then be converted to a saltthereof, preferably the hydrobromide salt.

[0041] If the precipitate formed is an oil or an amorphous solid, theprecipitation process may be repeated until a crystalline product isobtained. The crystals obtained are optionally recrystallised and thefree base of racemic citalopram may then be converted to a salt thereof,preferably the hydrobromide salt.

[0042] Depending on the ratio of R- and S-citalopram in the startingmaterial, it may be necessary to precipitate (in particular crystallise)citalopram free base more than once in order to obtain racemiccitalopram. The mother liquors from each precipitation may be pooledtogether and the citalopram enantiomer contained herein may be isolatedas described below.

[0043] Suitable solvents for the precipitation of the citalopram freebase are alkanes, such as heptane or hexane, alcohols, such asisopropanol, aromatic compounds such as toluene, benzene and xylene, ormixtures of alcohol and water and mixture of alkanes and alcohols. Thus,both aprotic and protic solvent may be useful.

[0044] If necessary crystallisation may be initiated by seeding withracemic crystalline citalopram base.

[0045] The precipitation of an acid addition salt of citalopram may becarried out by obtaining or dissolving the non-racemic mixture of R- andS-citalopram in a suitable solvent, if necessary by applying heating,and then adding an acid, either in a solution or as a gas. If crystalsare formed, the crystals are separated from the mother liquor,preferably by filtration. The crystals are optionally re-crystallised bydissolving the crystals in a solvent, preferably by heating, andallowing the solution to cool.

[0046] If the precipitate formed is not crystalline, but amorphous or anoil, the precipitation process may be repeated until a crystallineproduct is obtained. The crystals obtained are optionally recrystallisedas described above and the racemic citalopram salt may optionally beconverted into another salt thereof.

[0047] Depending on the ratio of R- and S-citalopram in the startingmaterial, it may be necessary to precipitate (in particular crystallise)the citalopram salt more than once in order to obtain a racemic mixture.The mother liquors from each precipitation or crystallisation may bepooled together and the citalopram enantiomer contained herein may beisolated as described below.

[0048] The acid used for precipitation of a citalopram salt is an acidwhich may precipitate a mixture of R- and S-enantiomer and leave themother liquor enriched with either the S- or R-enantiomer of citalopram.One such acid is hydrobromic acid.

[0049] Suitable solvents for the precipitation and recrystallisation ofcitalopram salts are protic solvents such as water, alcohols such asmethanol and ethanol, ketones such as acetone, and mixtures thereof oraprotic solvent such as acetonitrile or diglyme.

[0050] If necessary crystallisation may be initiated by seeding with theracemic crystalline citalopram salt.

[0051] Crystallisation of the free base or the hydrobromide salt ofcitalopram is preferred.

[0052] S-citalopram (or R-citalopram) may be isolated from the motherliquor using conventional procedures such as by evaporation of thesolvent from the mother liquor, or in case the mother liquor is acidicby basifying followed by separation of phases (if it is an oil) or byextracting S-citalopram (or R-citalopram) followed by evaporation of thesolvent. S-citalopram (or R-citalopram) may then be converted to a saltthereof, preferably the oxalate salt and optionally re-crystallised.

[0053] The mother liquor or extracts thereof may be subjected toconventional purification processes before evaporation of the solvent,or it may be subjected to one or more precipitations of citalopram freebase or citalopram salt according to the invention, in order to improvethe enantiomeric purity of the citalopram enantiomer product.

[0054] Likewise, an oily phase separated from the mother liquor may besubjected to conventional purification processes, or it may be subjectedto one or more precipitations of citalopram free base or citalopram saltaccording to the invention, in order to improve the enantiomeric purityof the citalopram enantiomer product.

[0055] In another aspect of the invention it has been found that ringclosure of the by-product of formula I in an acidic environment providesa reaction mixture containing a surplus of the S-enantiomer.

[0056] The process is illustrated in the reaction scheme below:

[0057] When the reaction is performed in the presence of an acid, amixture of R-citalopram and S-citalopram is obtained from R-diol. Thestereochemistry in this reaction is partly inverted, resulting insurplus of S-citalopram. The surplus amount of S-citalopram relative toR-citalopram is dependent upon the S/R ratio of the starting material asdemonstrated below. The ratio of inversion versus retention is around70:30 to 75:25 dependent on the reaction conditions of the experiment.

[0058] A surplus of S-citalopram will exist if an4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrilewith more than 50% of the R-enantiomer is used as the starting material.This resulting mixture can be further purified to give an S/R ratio ofmore than 95/5 by precipitation of the citalopram base from a solvent orby precipitation as an acid addition salt of citalopram from a solvent.A pure S-citalopram (S/R ratio more than 97/3) may be isolated from themother liquor, and precipitated as an acid addition salt with an acid,such as oxalic acid.

[0059] As mentioned above, the stereochemistry is partly inverted whenthe ring closure of R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrileis carried out in an acidic environment. Any suitable acid may be usefulfor this ring closure reaction. Good results were obtained with mineralacids such as sulphuric acid, HCl and phosphoric acid, and organic acidssuch as p-toluenesulphonic acid. In a preferred embodiment of theinvention, sulphuric acid is used. Preferably, surplus amount of acidrelative to starting material should be used.

[0060] The reaction can be performed in organic solvents suitable fordissolving the starting materials. Preferred solvents are solventssuitable for large-scale chemical production. Good results were obtainedusing toluene or acetonitrile.

[0061] When ring closure of the starting material of formula (1) isperformed via a labile ester intermediate, ie. in the presence oftosyl-chloride, in a basic environment, as described in EP-B1-347 066,the ring closing reaction proceeds with retention of thestereochemistry. The R-form of citalopram in an enantiomeric puritysubstantially equal to the starting material is then obtained.

[0062] This, thus-obtained R-form of citalopram can be optionally mixedwith a mixture of R and S-citalopram with an S-citalopram surplus toobtain racemic citalopram. Racemic citalopram may be obtained by one ormore precipitations of citalopram free base or a salt thereof, followedby recrystallisation as described above.

EXAMPLES

[0063] In the following examples optical purity is measured by ChiralHPLC.

Example 1

[0064] Preparation of Citalopram fromR-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(R/S ratio: 95.7/4.3) by Reaction with Different Acids in Acetonitrile

[0065] General Method:

[0066]R-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(67.5 g, R/S ratio: 95.7/4.3) dissolved in acetonitrile (37 g) wasstirred at room temperature, and a mixture of acid and ice (or water)was added (the quantity of acid and ice are listed in Table 1). Themixture was stirred at 78-85° C. (the reaction time have been listed inTable 1). The reaction mixture was cooled and water and toluene (315 mL)were added. Aqueous ammonia (25% by weight) was added to give a pH9.5-10.5 and the mixture was heated to 50-55° C. (5-10 minutes). Thephases were separated and to the water phase was added toluene (50 mL),and the phases was stirred at 50-55° C. (5-10 minutes). The phases wereseparated and the combined toluene phases were washed three times withwater (3×65 mL). The toluene was removed at reduced pressure at amaximum of 60° C. to give the product as an oil.

[0067] Citalopram was prepared by the general method above. The type ofacid and the quantities of acid and ice (water) in the acid mixture arelisted in Table 1. The percentage of the citalopram that isS-citalopram, analysed by chiral HPLC, is listed in Table 1 as well.TABLE 1 Citalopram by reaction with different acids in acetonitrile.Mass of Mass of ice or Reaction Percent S- Example Acid type acid waterin mixture time citalopram Yield 1 Sulphuric acid 25 g 10 g ice  3 hours73.4 65.6 g (˜100%) 2 Sulphuric acid 87 g 35 g ice  3 hours 72.0 57.0 g(89%) 3 Hydrochloric 22 g 11 g ice 24 hours >65 64.6 g acid (˜100%) 4 p-43 g 40 g water 48 hours 73.0 61.6 g Toluenesulfonic (95%) acid

Example 2

[0068] Preparation of Citalopram fromR-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(R/S ratio: 95.7/4.3) by Reaction with Different Acids in Toluene.

[0069] General method:R-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(67.5 g, R/S ratio: 95.7/4.3) was dissolved in toluene (315 mL). At roomtemperature, a mixture of acid and ice (or water) was added (thequantities of acid and ice are listed in Table 2). The mixture wasstirred at 78-85° C. (the reaction time have been listed in Table 2).The reaction mixture was cooled and water was added. Aqueous ammonia(25% by weight) was added to give a pH 9.5-10.5. The mixture was heatedto 50-55° C. (5-10 minutes). The phases were separated and the toluenephase was washed three times with water (3×65 mL). The toluene wasremoved at reduced pressure at a maximum of 60° C. The product was anoil.

[0070] Citalopram was prepared by the general method above. The type ofacid and the quantities of acid and water in the mixture are listed inTable 2. The percentage of the citalopram that is S-citalopram, analysedby chiral HPLC, is listed in Table 2 as well. TABLE 2 Citalopram byreaction with different acids in toluene. Mass of Mass of ice or PercentS- Example Acid type acid water in mixture Reaction time CitalopramYield 5 Sulphuric acid  26 g 10 g ice 70 minutes 73.8 61.8 g (97%) 6Phosphoric acid 275 g 11 g ice  4 hours 70.9 67.2 g (˜100%)

Example 3

[0071] Preparation of Citalopram HBr (racemic) fromR-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(R/S ratio: 95.7/4.3) by Combination of Products Obtained from theAcidic and the Basic Ring-Closure Methods.

[0072] Acidic Ring Closure:

[0073]R-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(67.5 g, R/S ratio: 95.7/4.3) was dissolved in toluene (315 mL). At roomtemperature, a mixture of sulphuric acid (26 g, 96%) and ice (10 g) wasadded. The mixture was stirred at 78-85° C. for 2 hours. The reactionmixture was cooled and 40 mL water was added. Aqueous ammonia (25% byweight) was added to give a pH 9.5-10.0. The mixture was heated to 55°C. (10 minutes). The phases were separated and the toluene phase waswashed three times with water (3×65 mL). The toluene was removed atreduced pressure at a maximum of 60° C. to give an oil (oil A). Yield:63 g (99%).

[0074] Basic Ring Closure of Labile Ester:

[0075]R-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(33.7 g, R/S ratio: 95.7/4.3) was dissolved in acetonitrile (16 g) andtoluene (135 mL). 21.4 g Triethylamin was added. A solution oftosylchlorid (19.7 g) and toluene (55 mL) was added to the mixture at arate so that the temperature was kept bellow 50° C. The mixture wasstirred at 10° C. for 20 minutes. Water (75 mL) was added and themixture was stirred for 5 minutes. Aqueous ammonia (25% by weight) wasadded to give a pH of 9.5. The phases were separated and toluene (35 mL)was added to the water phase. This was stirred for 10 minutes at 45° C.The toluene phases were combined and washed with water (2×75 mL). Thetoluene was removed at reduced pressure at a maximum of 50° C. to givean oil (oil B). Yield: 32.3 g (˜100%).

[0076] Precipitation of a Mixture of Oils A and B.

[0077] Oil A (57 g) and oil B (28 g) were mixed by dissolving in acetone(310 mL) at room temperature. 35 mL of the solution was removed, HPLCshowed an S/R ratio of 49.6/50.4. The mixture was cooled. The pH was3-4.5. 15 mL of the solution were removed before addition of hydrogenbromide. Gaseous hydrogen bromide was added until pH was 1.5. Themixture was cooled to 15° C. and stirred overnight. The crystals werefiltered and washed with a mixture of acetone (70 mL) and hexane (70mL). After drying, a yield of 75.7 g (71%) crystals was obtained. Thepurity of the crystals was 99.2% (HPLC) and the S/R ratio was 49.5/50.5(Chiral HPLC).

[0078] Recrystallisation in Water

[0079] Crystals (29.9 g) from the precipitation of oils A and B weredissolved in 75 mL water at about 48° C. The solution was cooled andseeded, and it was stirred for 2½ day at room temperature. The mixturewas cooled to 8° C. The crystals were filtered off and washed with water(24 mL). After drying, a yield of 27.9 g (93.3%) Citalopram HBr(racemic) was obtained. The purity of the crystals was 99.4% (HPLC) andthe S/R ratio was 50/50% (Chiral HPLC), hence a racemic substance wasobtained.

Example 4

[0080] Preparation of S-citalopram oxalate fromR4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(R/S ratio: 95.7/4.3).

[0081] Ring Closure in Presence of Sulphuric Acid

[0082]R-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(67.0 g, R/S ratio: 95.7/4.3%) was dissolved in toluene (315 mL). Atroom temperature, a mixture of sulphuric acid (25 g, 96%) and ice (10 g)was added. The mixture was stirred at 80-85° C. for 1 hour and 40minutes. The reaction mixture was cooled to room temperature and water(40 mL) was added. Aqueous ammonia (50 mL, 25% w/w) was added to adjustpH to 10.5. The mixture was heated to 55° C. (10 minutes). The phaseswere separated and the toluene phase was washed three times with water(3×65 mL). The toluene was removed at reduced pressure at a maximum of60° C. to an oil. Yield: 60.4 g (95%).

[0083] The oil (60.4 g) was dissolved in heptane (600 mL) by heating to89° C. The mixture was allowed to cool to room temperature and stirredover-night. The mixture was filtered. The mother liquor was evaporatedand the yield was 20.4 g (34%). The mother liquor was dissolved inethanol (78 mL) and the mixture was cooled to <25° C. A solution ofoxalic acid anhydrate (10.2 g) in ethanol (48 mL) was added. The mixturewas stirred for 3 hours at <15° C. The mixture was filtered and washedwith ethanol (24 mL). After drying, a yield of 19.9 g (76%) wasobtained. The purity of the crystals was 96.8% (HPLC) and the S/R ratiowas 97.6/2.4 (Chiral HPLC).

Example 5

[0084] Preparation of Citalopram fromR-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(R/S ratio: 69.0/31.0) by Reaction with Sulphuric Acid in Acetonitrile.

[0085]R-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(31.1 g, R/S ratio: 69.0/31.0) dissolved in acetonitrile (420 g) wasstirred at room temperature and a mixture of sulphuric acid (50 g, 96%)and ice (17 g) was added. The mixture was stirred at 78-80° C. for 1hour. The reaction mixture was cooled and water and toluene (160 mL)were added. Aqueous ammonia (25% by weight) was added to give a pH of10.5. The mixture was heated to 50-55° C. (5-10 minutes). The phaseswere separated and to the water phase was added toluene (25 mL) and itwas stirred at 50-55° C. (5-10 minutes). The phases were separated andthe combined toluene phases were washed three times with water (3×50mL). The toluene was removed at reduced pressure at a maximum of 60° C.The product was an oil. Yield: 32.9 g (90%). The purity of theevaporated mother liquor was 96.9% and the S/R ratio was 59.5/40.5(Chiral HPLC).

Example 6

[0086] Preparation of Citalopram fromS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(S/R ratio: 99.1/0.9) by Reaction with Sulphuric Acid in Toluene.

[0087]S-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile(67.0 g, S/R ratio: 99.1/0.9) was dissolved in toluene (315 mL). At roomtemperature a mixture of sulphuric acid (25.8 g, 96% and ice (10.7 g)was added. The mixture was stirred at 78-85° C. for 2 hours. Thereaction mixture was cooled and water (40 mL) was added. Aqueous ammonia(50 mL, 25% by weight) was added to give a pH 10.5-11.0. The mixture washeated to 57° C. (10 minutes). The phases were separated and the toluenephase was washed three times with water (3×65 mL). The toluene wasremoved at reduced pressure at a maximum of 60° C. The product was anoil. Yield: 63.9 g (˜100%). The purity of the oil was 94.9% and the S/Rratio was 26.3/73.7 (Chiral HPLC).

Example 7

[0088] Purification of S-Citalopram by Precipitation of the Free Base

[0089] Precipitation experiments were conducted to determine howefficient the process was for the removal of small amounts of mixturesR- and S-citalopram from S-citalopram. See Table 3 for the results. Thegeneral procedure was as follows. To a mixture of S- and R-citalopram(as described in the “Before precipitation” column) was added heptane(10 mL/1 g citalopram). The mixtures were warmed to reflux, whereuponthe citalopram samples dissolved. Heating was stopped, and the sampleswere allowed to cool to room temperature slowly. In all cases, somematerial fell out of solution. Where there was a large amount of theR-citalopram in the starting material, the residue was generally asolid, but where there was only a small amount of the R-citalopram inthe starting material, the residue was generally an oil. In all casesthe mother liquor was removed by filtration (or decanting, in the caseof an oily precipitate). The R/S ratios of the precipitates are shown inTable 3. The filtrates were evaporated to give oils/amorphous solids.The R/S ratios of these oils/amorphous solids are shown in the columns“Oil/amorphous solid after evaporation” in Table 3. In all cases, theproducts were analysed by chiral SCFC HPLC. TABLE 3 Precipitation of thefree racemic citalopram base After Precipitation Before PrecipitateOil/amorphous solid Precipitation (mixture of after evaporation MixtureofIsomers R and S-citalopram (enriched S-enantiomer) S % R % S % R % S %R % 98.2 1.8 99 1.3 98.1 1.9 97.5 2.5 98 2.5 96.9 3.1 95.4 4.6 82 17.698.8 1.2 94.2 5.8 66 34 98.5 1.5 89.0 11 65 35 98.5 1.5 80.3 19.7 54 4698.4 1.6 61.0 39 53 47 96.7 3.3

[0090] Inspection of the last 5 rows in Table 3 shows that when theratio S/R in the starting material is less than 97/3, a substantialenrichment of the S-isomer occurs in the oil after evaporation of thefiltrate. In all cases, the ratio of S/R in the final product is >95/5.

Example 8

[0091] Purification of S-Citalopram by Precipitation of Citalopram asthe Hydrobromide Salt

[0092] A mixture of citalopram isomers was dissolved in iso-propylalcohol (IPA) (10 ml IPA/1 g citalopram). A solution of anhydrous HBr inIPA (2.0 eq, 5.2 M) was added dropwise, and the solutions were seededwith racemic citalopram HBr crystals. The solutions were stirredovernight and filtered. The filtrate was evaporated to give anoil/amorphous solid. The results of these experiments are shown in Table4. “Before Precipitation” refers to the composition of the mixturebefore addition of HBr, and “After Precipitation” refers to the twoproducts isolated after filtration. No crystalline material was isolatedin the first case (where the “Mixture of Isomers” was S: 98.2% and R:1.8%). The products were analysed by chiral SCFC HPLC. TABLE 4Crystallisation of citalopram HBr salt After Precipitation Crystallinesolid Oil after evaporation of Before Precipitation from IPA (mixture ofIPA Mixture of Isomers R and S-citalopram) (enriched S-citalopram) S % R% S % R % S % R % 98.2 1.8 98.7 1.3 97.5 2.5 75 25 >99.9 <0.1 95.4 4.669 31 >99.9 <0.1 94.2 5.8 68 32 >99.9 <0.1 89.0 11 69 31 >99.9 <0.1 78.721.3 65 35 98.9 1.1 80.3 19.7 60 40 98.4 1.6 61.0 39 56 44 96.7 3.3

[0093] In almost all cases, there was virtually no R-isomer remaining inthe mother liquor, and the yield of the precipitates and the oils afterevaporation reflect this. Inspection of the first column and the secondlast column indicates that in most cases, substantial enrichment of theS-isomer occurred, and that in all cases the S/R ratio of the oil afterevaporation was greater than 96/4.

1. A process for the preparation of racemic citalopram free base or anacid addition salt thereof and/or R- or S-citalopram as the free base oran acid addition salt thereof by separation of a mixture of R- andS-citalopram with more than 50% of one of the enantiomers into afraction consisting of racemic citalopram and/or a fraction ofS-citalopram or R-citalopram characterized in that i) citalopram isprecipitated from a solvent as the free base or as an acid addition saltthereof; ii) the precipitate formed is separated from the mother liquor;iia) if the precipitate is crystalline it is optionally recrystallizedone or more times to form racemic citalopram, and then optionallyconverted into an acid addition salt thereof; iib) if the precipitate isnot crystalline, steps i) and ii) are optionally repeated until acrystalline precipitate is obtained and the crystalline precipitate isoptionally recrystallized one or more times to form racemic citalopram,and then optionally converted into an acid addition salt thereof; andiii) the mother liquor is optionally subjected to further purificationand S-citalopram or R-citalopram is isolated from the mother liquor andoptionally converted into an acid addition salt thereof.
 2. A processaccording to claim 1 for the preparation of S-citalopram or R citalopramcharacterized in that i) citalopram in the mixture of R- andS-citalopram is precipitated from a solvent as the free base or as anacid addition salt thereof; ii) the precipitate formed is separated fromthe mother liquor, and iii) the mother liquor is optionally subjected tofurther purification and S-citalopram or R-citalopram is isolated fromthe mother liquor and optionally converted into an acid addition saltthereof.
 3. A process according to claim 1 for the preparation ofracemic citalopram characterized in that i) citalopram in the mixture ofR- and S-citalopram is precipitated from a solvent as the free base oras an acid addition salt thereof; and ii) the precipitate formed isseparated from the mother liquor, iia) if the precipitate is crystallineit is optionally recrystallized one or more times to form racemiccitalopram, and then optionally converted into an acid addition saltthereof; iib) if the precipitate is not crystalline, steps i) and ii)are repeated until a crystalline precipitate is obtained and thecrystalline precipitate is optionally recrystallized one or more timesto form racemic citalopram, and optionally converted into an acidaddition salt thereof.
 4. The method according to claim 1 characterizedin that the acid used for precipitation of citalopram in step i) is anacid which precipitate a mixture of R- and S-enantiomer and leave themother liquor enriched with either the S- or R-enantiomer of citalopram.5. The process according to claim 1 wherein the salt precipitated in instep i) is the hydrobromide salt.
 6. The process according to claim 1wherein the free base is precipitated in step i).
 7. The processaccording to claim 1 characterised in that the mixture of R- andS-citalopram with more than 50% of one of the enantiomers contains morethan 50% of S-citalopram.
 8. The process according to claim 12characterized in that S citalopram is isolated from the mother liquor byevaporation and thereafter optionally lo converted to an acid additionsalt thereof.
 9. The process according to claim 1 characterized in thatthe mother liquor is acidic and S-citalopram is isolated from the motherliquor by basifying the mother liquor, followed by phase separation orextraction with a solvent and evaporation of the solvent, and thereafteroptionally conversion of S-citalopram into an acid addition saltthereof.
 10. The process of claim 1 wherein the mother liquor issubjected to one or more further precipitations of citalopram asdescribed under step i) before isolation of the R- or S-citalopram fromthe mother liquor.
 11. The process according to claim 1 characterized inthat a mixture of R- and S-citalopram with more than 50% of theS-enantiomer is prepared from a mixture I of R- andS-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-32s(hydroxymethyl)-benzonitrile with more than 50% of the S-enantiomer byformation of a labile ester group and thereafter ring closure in a basicenvironment.
 12. The process according to claim 1 characterized in thata mixture of R- and S-citalopram with more than 50% of the R-enantiomeris prepared from a 30 mixture of R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3(hydroxymethyl)-benzonitrile with more than 50% of the R-enantiomer byformation of a labile ester group and thereafter ring closure in a basicenvironment.
 13. The process according to claim 1 characterized in thata mixture of R- and S-citalopram with more than 50% of the S-enantiomeris prepared from a mixture of R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethyl)-benzonitrilewith more than 50% of the R-enantiomer by ring closure in presence of anacid.
 14. The process according to claim 1 characterized in that amixture of R- and S-citalopram with more than 50% of the R-enantiomer isprepared from a mixture of R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3′ e(hydroxymethyl)-benzonitrile with more than 50% of the S-enantiomer byring closure in presence of an acid.
 15. A process for the preparationof a mixture of R- and S citalopram with more than 50% of theS-enantiomer characterized in that a mixture of R- and S-4-[4 5(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrilewith more than 50% of the R-enantiomer is subjected to ring closure inpresence of an acid.
 16. A process for the preparation of a mixture ofR- and S-citalopram with more 20 than 50% of the R-enantiomercharacterized in that a mixture of R- andS-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrilewith more than 50% of the S-enantiomer is subjected to ring closure inpresence of an acid.
 17. The process according to claim 12 characterizedin that the starting material contain more than 90% ofR-4-[4-(dimethylamino)-1-(4′-Ifluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile compared toS-4-[4(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile.18. The process according to claim 13 characterized in that the acidused in I the ring-closure reaction is a mineral acid, a carboxylicacid, a sulfonic acid or I sulfonic acid derivative.
 19. The processaccording to claim 18 characterised in that the acid is H₂SO₄ or H₃PO₄.20. The process according to claim 5, wherein the hydrobromide salt isin crystalline form.
 21. The process according to claim 7, wherein themixture of R- and S-citalopram with more than 50% of one of theenantimoers contains more than 90% of S-citalopram.
 22. The processaccording to claim 8, wherein the acid addition salt is the oxalatesalt.
 23. The process according to claim 9, wherein the acid additionsalt is the oxalate salt.
 24. The process of claim 13 characterized inthat the starting material contain more than 90% ofR-4-[4-(dimethylamino)-1-(4′-Ifluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile compared toS-4-[4(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile.25. The process of claim 15 characterized in that the starting materialcontain more than 90% of R-4-[4-(dimethylamino)-1-(4′-Ifluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile compared toS-4-[4(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile.